Chiral sensor

ABSTRACT

An optically active compound having an unsaturated bond at an optically active binding site, wherein the unsaturated bond and a fluorescent substituent or a substituent capable of imparting fluorescence are united in a conjugated manner; and a chiral sensor comprising the optically active compound as defined above. The chiral sensor can highly selectively recognize a specified chiral compound in high sensitivity.

TECHNICAL FIELD

The present invention relates to an optically active compound and achiral sensor comprising the compound. More specifically, the presentinvention relates to an optically active compound capable of recognizinga chiral compound in a high sensitivity and a chiral sensor comprisingthe compound. The chiral sensor is useful in separation or sensing inconnection with its relationship with physiological activities foramines, amino acids and amino alcohols, sensing for the detection of anarcotic drug and the designation of the producing district, or thelike.

BACKGROUND ART

Medicaments having optical isomers have been required to be developed asoptical pure compounds from the viewpoint of adverse actions or thelike. Therefore, the significance of optical resolution and examinationof optical purity has been becoming increasingly high.

Especially, optically active amines such as ethanolamine derivatives andcatecholamine derivatives have physiological activities for the centralnervous system, and are important compounds as numerous medicamentintermediates. Therefore, conventionally, numerous studies have beenmade on the complexation for recognizing enantiomers on the bases ofhost-guest interactions using crown ethers for optical resolution oranalytical purposes of optically active amines [X. X. Zhang, J. S.Bradshaw, R. M. Izatt: Chem. Rev., 97, 3313-3361 (1997): K. Hirose, J.Incl. Phenom. and Macrocyclic Chem., 39, 193-209 (2001). and the like].However, these complexes have low sensitivities, so that they are hardlyused in practical purposes.

Chiral sensors which have been recently developed are those in a chainform containing binaphthol in the molecule (J. Lin, Q.-S. Hu, M.-H. Xu,L. Pu, J. Am. Chem. Soc., 124, 2088-2089 (2002): J. L. Tian, J. C. Yong,S. Z. Ke, D. Wang, W. G. Da, Z. Y. Xiao, Chirality, 13, 595-600 (2001):D. Wang, T.-J. Liu, W.-C. Zhang, W. T. Slaven, C.-J. Li, Chem. Commun.,1998, 1747-1748), and those having a dendrimer form (V. J. Pugh, Q.-S.Hu, L. Pu, Angew. Chem. Int. Ed., 39, 3638-3641 (2000): L.-Z. Gong,Q.-S. Hu, L. Pu, J. Org. Chem., 66, 2358-2367 (2001)). When these chiralsensors are used, the sensors have high sensitivities utilizingfluorescence emission. However, these chiral sensors do not haveselectors (binding sites) which are easily prepared and have highselectivity, so that these sensors are hardly used in practicalpurposes.

In addition, most of the natural amino acids and the physiologicallyactive substances are chiral compounds. However, under the currentsituation, the development of sensors capable of rapidly recognizingthese chiral compounds in high sensitivity have been earnestly desired.This development is based on the fact that it is very difficult tosatisfy high binding property and high selectivity against an enantiomertarget of a receptor, in the conventional sensors.

DISCLOSURE OF INVENTION

An object of the present invention is to provide a practically veryuseful chiral sensor capable of recognizing with high selectivity aspecified chiral compound in a high sensitivity.

The present invention relates to:

-   [1] an optically active compound having an unsaturated bond at an    optically active binding site, wherein the unsaturated bond and a    fluorescent substituent or a substituent capable of imparting    fluorescence are united in a conjugated manner; and-   [2] a chiral sensor comprising the optically active compound as    defined above.

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors have prepared numerous optically active crownethers having a pseudo-18-crown-6 framework, and performed studies onthe formation of complexes for recognizing enantiomers in the solution.As a result, they have successfully developed a phenolic crown etherhaving a high enantioselectivity especially for ethanolaminederivatives. This compound has features that {circle over (1)} thecompound can be prepared from a commercially available, inexpensivechiral compound, that {circle over (2)} the compound has a phenol moiety(acidic), so that the compound binds with a neutral amine to form asalt-complex, that {circle over (3)} the absorption spectrum changeswith the formation of the salt-complex, and the like.

Numerous compounds were prepared, and the position of a chiral centerand the substituent of the chiral center of the crown ether ring havebeen optimized. As a result, it has been found that a host molecule 1 inthe formula:

is excellent in all the features. The host molecule 1 forms asalt-complex 3 with an amino alcohol 2.

In this example, the R/S ratio of the complex stability constant at roomtemperature reaches 13-folds. The high enantioselectivity of this hostmolecule 1 is reflected in a great difference in the absorption spectrumbased on a phenolate salt-complex near 560 nm in the visible absorptionspectrum.

While the present inventors pursued the studies for further improvingthe selectivity, the host for recognizing enantiomers has been developedfor practical use. As a result, when a chiral selector represented bythe formula:

is applied to chromatography for separation of optical isomers, thepractical use as a chemically bonded type optically active column hasbeen successfully accomplished for the first time in the world. Thischiral selector has a sufficiently high enantiomer-recognizing abilityas a chiral selector for the optically active column.

As described above, there have been verified that the pseudo-18-crown-6type host compound has a very high enantiomer-recognizing ability, andthat its cost is bearable for practical purposes by optimizing thechiral site.

Next, the present inventors have considered that the development ofmeasures for improving enantiomer-recognizing ability based on a newprinciple is required in order that an analyte is detected in an evenhigher sensitivity, and that the selectivity is further enhanced.Therefore, they have remarked on the fluorescence spectrum.

In general, fluorescent host compounds have been developed and appliedto microanalysis by utilizing the excellent sensitivity. The presentinventors have developed a fluorescent new host having selectivityamplifying effects by skillfully utilizing the feature of emissionproperty and equilibrium reaction of host-guest complexation in additionto the high sensitivity of the fluorescent host compound.

This compound is an optically active compound having an unsaturated bondat an optically active binding site, wherein the unsaturated bond and afluorescent substituent or a substituent capable of impartingfluorescence are united in a conjugated manner. This compound is usefulas a chiral sensor.

Representative examples of the above-mentioned optically active compoundinclude a compound represented by the formula (I):

wherein R¹ is an aromatic group or an aromatic ethynyl group; R² is ahydrogen atom or an alkyl group having 1 to 10 carbon atoms; each of R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ is independently a hydrogen atom, or analkyl group having 1 to 30 carbon atoms, a cyclic alkyl group having 3to 30 carbon atoms or an aryl group having 6 to 30 carbon atoms, each ofwhich may have a substituent, with proviso that each of R⁴ and R⁵, andR⁸ and R⁹ may be bonded to form an alkylene group having 2 to 60 carbonatoms; and each of R¹¹ and R¹² is independently a hydrogen atom or analkyl group having 1 to 15 carbon atoms which may have a hetero-atom,with proviso that R¹¹ and R¹² may be bonded to form an alkylene grouphaving 2 to 30 carbon atoms which may have a hetero-atom.

In the formula (I), R¹ is an aromatic group or an aromatic ethynylgroup.

The aromatic group includes, for instance, an aryl group having 6 to 20carbon atoms, preferably 6 to 16 carbon atoms, such as a phenyl group, atolyl group, a xylyl group, a biphenyl group, a naphthyl group, ananthryl group, a phenanthryl group, and a pyrenyl group; an aryl grouphaving 6 to 20 carbon atoms, preferably 6 to 16 carbon atoms, having ahetero-atom, such as a benzothiazolyl group and a naphthothiazolylgroup; and the like. Among them, a naphthyl group, an anthryl group, aphenanthryl group, a pyrenyl group and a benzothiazolyl group arepreferred.

The aromatic ethynyl group includes, for instance, an arylethynyl grouphaving 8 to 22 carbon atoms, preferably 8 to 18 carbon atoms, such as aphenylethynyl group, a tolylethynyl group, a xylylethynyl group, abiphenylethynyl group, a naphthylethynyl group, an anthrylethynyl group,a phenanthrylethynyl group, and a pyrenylethynyl group; an arylethynylgroup having 8 to 22 carbon atoms, preferably 8 to 18 carbon atoms,having a hetero-atom, such as a benzothiazolylethynyl group and anaphthothiazolylethynyl group; and the like. Among them, a phenylethynylgroup, a naphthylethynyl group, an anthrylethynyl group, aphenanthrylethynyl group, a pyrenylethynyl group and abenzothiazolylethynyl group are preferred.

R² is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.Among them, a hydrogen atom and a methyl group are preferable.

Each of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ is independently a hydrogenatom, or an alkyl group having 1 to 30 carbon atoms, a cyclic alkylgroup having 3 to 30 carbon atoms or an aryl group having 6 to 30 carbonatoms, each of which may have a substituent, with proviso that each ofR⁴ and R⁵, and R⁸ and R⁹ may be bonded to form an alkylene group having2 to 60 carbon atoms. The above-mentioned substituent includes, forinstance, a hydroxyl group, a thiol group, an amino group, a nitrogroup, a halogen atom (for instance, a fluorine atom, a chlorine atom, abromine atom, and an iodine atom), and the like. It is preferable thateach of R³, R⁴, R⁵, R⁷, R⁸ and R⁹ is a hydrogen atom.

Examples of R⁶ and R¹⁰ include an aryl group having 6 to 30 carbonatoms, preferably 6 to 12 carbon atoms, such as a phenyl group and a1-naphthyl group; and a cyclic alkyl group having 3 to 30 carbon atoms,preferably 3 to 10 carbon atoms, such as a 1-adamantyl group; and thelike. Preferred examples of R⁶ and R¹⁰ include a phenyl group, a1-naphthyl group, a 1-adamantyl group, a 1-(3,5-dimethyl)phenyl groupand a 1-bi-2-naphthyl group, among which a phenyl group is preferable.

Each of R¹¹ and R¹² is independently a hydrogen atom or an alkyl grouphaving 1 to 15 carbon atoms which may have a hetero-atom, with provisothat R¹¹ and R¹² may be bonded to form an alkylene group having 2 to 30carbon atoms which may have a hetero-atom. The above-mentionedhetero-atom includes, for instance, an oxygen atom, a sulfur atom,nitrogen atom and the like. Preferred R¹¹ and R¹² include a group inwhich R¹¹ and R¹² are bonded to form a group represented by the formula:—[(CH₂)_(p)—O—(CH₂)_(q)]_(r)—,wherein each of p, q and r is independently an integer of from 1 to 15.

Among the above-mentioned optically active compounds, a preferredcompound is a compound represented by the formula (III):

wherein R¹ and R² are as defined above,as representatively exemplified by the formula (II):

The basic structures of the compound represented by the formula (II) arephenolic pseudo-18-crown-6 hosts having two asymmetric carbon atoms, inwhich phenylacetylene is introduced into a para-position of the phenolichydroxy group to make the host fluorescent, and at the same time thedegree of acidity of the phenolic hydroxy group is adjusted to a levelsufficient for forming a salt with an amine.

An important feature in the design of the optically active compound ofthe present invention resides in that the fluorescence emission band ofthe host overlaps with the absorption band of the complex.

Consequently, three quenching processes can be considered:

-   {circle over (1)} quenching by complex formation in a ground state    (static quenching);-   {circle over (2)} quenching by interaction in an excited state    (dynamic quenching); and-   {circle over (3)} quenching by reabsorption of the fluorescence    emission of the host by the complex (reabsorption quenching)

The effect of {circle over (3)} mentioned above acts so that theenantioselectivity is always amplified, and the selectivity can beamplified by the effect of {circle over (2)} mentioned above.

In the optically active compound of the present invention, the compoundrepresented by the formula (II) can be obtained, for instance, througheight steps from (S)-mandelic acid by the preparation route as describedin the following scheme:

More specifically, the optically active compounds of the presentinvention can be prepared by the methods set forth in the followingexamples. These examples are one example of the embodiments of thepresent invention, so that the present invention is not limited to theseexamples alone.

Thus, the optically active compound having an unsaturated bond at anoptically active binding site, wherein the unsaturated bond and afluorescent substituent or a substituent capable of impartingfluorescence are united in a conjugated manner, as representativelyexemplified by the compound represented by the formula (I), can beobtained.

The chiral sensor of the present invention comprises the above-mentionedoptically active compound. The chiral sensor of the present inventionmay be one in which the above-mentioned optically active compound isdirectly used, or one in which the optically active compound isdissolved in a solvent. Alternatively, the chiral sensor may be, forinstance, in the form such that the above-mentioned optically activecompound is kneaded with a thermoplastic resin such as polyethylene,polypropylene or polystyrene and formed into a film such as a porousfilm, or molded into a molded article of desired shape and size, such asbeads, pellets or plates; and the like. Further, the chiral sensor ofthe present invention may be, for instance, in the form such that apolymer obtained by introducing a polymerizable group such as an allylgroup, as representatively exemplified by, for instance, a vinyl group,to the group represented by R¹ in the formula (I), and subjecting thecompound represented by the formula (I) to homo-polymerization by thepolymerizable group, or co-polymerization of the compound with othermonomers is formed into a film such as a porous film, or molded into amolded article of desired shape and size, such as beads, pellets orplates; and the like. As described above, the chiral sensor of thepresent invention can be used in a wide range in various forms.

The chiral sensor of the present invention can be used, for instance, asa chiral sensor for a low-concentration substance requiring both highsensitivity and high selectivity by monitoring fluorescence emission inthe absorption band of the complex in the long-wavelength side than theexcitation light.

Since the chiral sensor of the present invention is capable of highlyselectively recognizing a specified chiral compound in high sensitivity,the chiral sensor is very useful for practical purposes. For instance,the chiral sensor can be suitably used in separation or sensing inconnection with its relationship with physiological activities foramines, amino acids and amino alcohols, sensing for the detection of anarcotic drug and the designation of the producing district or the like.

Next, the present invention will be described more specifically based onExamples, without intending to limit the present invention thereto.

Here, the spectroscopic devices used in the following Examples are asfollows.

-   (a) NMR Spectrum: Nuclear Magnetic Resonance Spectrum one    manufactured by JASCO Corporation, JEOL JNM-GSX-270-   (b) IR Spectrum:    one manufactured by JASCO Corporation, JASCO Fourier transform    infrared spectrophotometer FT/IR-410-   (c) Optical Rotation:    one manufactured by JASCO Corporation, JASCO Digital Polarimeter    DIP-370-   (d) Melting Point:    a hot plate equipped with a microscope-   (e) Mass Spectrum:    one manufactured by Shimadzu Corporation, SHIMADZU LCMS-2010-   (f) Open Column Chromatography:    one manufactured by MERCK, Silica-gel 60 (70-230 mesh ASTM)-   (g) Recycling High-Performance Liquid Chromatography:    one manufactured by Japan Analytical Industry Co., Ltd. (JAI),    LC-908 20 mm JAUGEL-1H, 2H GPC-   (h) Thin-Layer Chromatography:    one manufactured by MERCK, Silica-gel 60 F₂₅₄

EXAMPLE 1 Preparation of Chiral Unit (S)-4

A 1-L three-neck flask was charged with methanol (300 mL, 7.41 mol) and(S)-(+)-mandelic acid 5 (50.2 g, 330 mmol) while stirring, and themixture was cooled to 0° C. in an ice-salt bath. Thereafter, thionylchloride (27.0 mL, 379 mmol) was gradually added dropwise thereto from adropping funnel. After the termination of the dropwise addition, thetemperature of the mixture was recovered to an ambient temperature, atwhich the mixture was stirred for 23 hours.

Next, excess thionyl chloride and methanol were distillated underreduced pressure. Thereafter, the residue was extracted with chloroform,and an organic layer was washed with water and with saturated brine, andthe mixture obtained was dried over anhydrous magnesium sulfate, andthereafter concentrated, thereby giving methyl (S)-(+)-mandelate (S)-6(47.5 g, 286 mmol) in the form of a white solid.

A 1-L eggplant-shaped flask equipped with a calcium chloride tube wascharged with chloroform (700 mL) and methyl (S)-(+)-mandelate (S)-6(47.3 g, 285 mmol), and thereafter dihydropyran (100 mL, 1.07 mol) wasadded thereto, while stirring for 40 minutes in an ice bath, andpyridinium p-toluenesulfonate (3.56 g, 14.2 mmol) was added thereto. Thetemperature of the mixture was recovered to room temperature, and themixture was stirred for 3 hours. Thereafter, the mixture was washed withwater and with saturated brine, and the mixture obtained was dried overanhydrous magnesium sulfate and concentrated, to give an yellowish oilycrude product (S)-7 (93.9 g).

A 1-L three-neck flask was charged with anhydrous tetrahydrofuran (500mL) under nitrogen gas stream, and the content was cooled to −20° C. ina dry ice-oil bath. Thereafter, lithium aluminum hydride (6.92 g, 182mmol) was gradually added thereto.

Next, a solution prepared by dissolving the yellowish oily crude product(S)-7 (32.9 g) in anhydrous tetrahydrofuran (50 mL) was gradually addeddropwise to the above-mentioned solution over a period of 1 hour, andthe mixture was stirred at room temperature for 3 hours. Thereafter, themixture obtained was again cooled to −20° C. in the dry ice-oil bath,and acetone (45 mL) was added thereto to stop the reaction.

After the solution was stirred overnight, this solution was subjected tosuction filtration, and each of a solid portion and a filtrate portionwas extracted with hexane-ethyl acetate. The organic layer was washedwith saturated brine. Thereafter, the mixture obtained was dried overanhydrous magnesium sulfate, and concentrated, to give (S)-4 (24.9 g,112 mmol) in the form of a pale yellowish oily product (yield: 97%).

EXAMPLE 2 Preparation of Tribromide 8

A 3-L Erlenmeyer flask shielded by covering the flask with an aluminumfoil was charged with sodium hydroxide (135 g, 3.27 mol) and water (540mL), while cooling, and the contents were completely dissolved.p-Bromophenol (508 g, 2.85 mol) was added thereto and completelydissolved. The temperature of the mixture was recovered to roomtemperature, a 37% aqueous formaldehyde solution (1200 mL, 16.1 mol) wasadded thereto, and the mixture was allowed to stand for 12 days. Themixture was cooled in an ice bath, and a 3 N sulfuric acid was addeddropwise thereto while thoroughly stirring the mixture with a mechanicalstirrer. The precipitated solid obtained by allowing the mixture tostand for 5 hours was subjected to suction filtration, and the residuewas washed with water, and air-dried, to give a crude product (848 g) ofa triol form 10.

A 3-L three-neck flask was charged with acetone (2 L), potassiumcarbonate (100 g, 720 mmol), a product (103 g) prepared by pulverizingthe crude triol product 10 obtained above, and dimethyl sulfate (43.0mL, 431 mmol). The contents were refluxed with heating for 3 hours,while warming with a hot water bath at 60° C. The temperature of themixture was recovered to room temperature, and thereafter, water (500mL) was added thereto. Acetone was distilled off under reduced pressurewith a rotary evaporator. The precipitated solid was subjected tosuction filtration, washed with water, and then air-dried, to give acompound 11 (117 g).

A 3-L three-neck flask containing a 48% aqueous hydrogen bromide (2 L)was charged with the resulting compound 11 (59.2 g). The mixture wasstirred for 4 hours with a mechanical stirrer while warming the mixtureat 60° C. The temperature of the mixture was recovered to roomtemperature, and water (500 mL) was added thereto. The precipitatedbeige color solid was subjected to suction filtration. The residue wasdissolved in a proper amount of chloroform, and the solution wasfiltered in a silica gel, and concentrated, thereby giving a tribromide8 (53.3 g, 142 mmol) in the form of a white solid (yield: 73%).

¹H-NMR (270 MHz, CDCl₃, 30° C.) δ: 4.00 ppm (3H, s, OMe), 4.48 (4H, s,benzyl), 7.49 (2H, s, ArH)

EXAMPLE 3 Preparation of Diethylene Glycol Ditosylate 12

A 500 mL eggplant-shaped flask was charged with diethylene glycol 13(15.0 mL, 155 mmol) and pyridine (300 mL), and p-toluenesulfonylchloride (68.0 g, 351 mmol) was gradually added thereto in an ice bath.The mixture was stirred for 4 hours in the ice bath. Thereafter, a 1-LErlenmeyer flask containing ice was charged with the reaction solution,and a concentrated hydrochloric acid (220 mL) was added thereto in theice bath to adjust its pH to 4. The reaction mixture was subjected tosuction filtration, and thereafter the residue was dissolved inchloroform. The mixture obtained was dried over anhydrous magnesiumsulfate and concentrated, to give a product 12 (54.4 g, 131 mmol) in theform of a white solid (yield: 85%).

¹H-NMR (270 MHz, CDCl₃, 30° C.) δ: 2.45 ppm (6H, s, CH₃), 3.61 (4H, t,—CH₂—), 4.10 (4H, t, —CH₂—), 7.34 (4H, d, J=8.3 Hz, ArH), 7.78 (4H, d,J=8.3 Hz, ArH)

EXAMPLE 4 Preparation of Diol Form (S,S)-14

A 1-L three-neck flask was charged with anhydrous tetrahydrofuran (250mL) and 60% sodium hydride (5.41 g, 135 mmol) under a nitrogen gasstream. A solution prepared by dissolving (S)-4 (19.1 g, 85.9 mmol) inanhydrous tetrahydrofuran (130 mL) was added dropwise thereto over aperiod of 1 hour. The mixture was refluxed at 60° C. for 30 minutes, andthereafter a solution prepared by dissolving the compound 8 in anhydroustetrahydrofuran (130 mL) (12.2 g, 32.7 mmol) was added dropwise theretoover a period of 1.5 hours. The mixture obtained was stirred overnightin this state. Heating was stopped, and water (20 mL) was graduallyadded dropwise thereto in an ice bath to terminate the reaction.Thereafter, the solution was concentrated under reduced pressure. Thisresidue was extracted with hexane-ethyl acetate, and the organic layerwas washed with saturated brine. Thereafter, the mixture obtained wasdried over anhydrous magnesium sulfate and concentrated, to give areddish brown oily product (26.8 g).

This formed product was transferred to a 500 mL eggplant-shaped flaskequipped with a calcium chloride tube. The flask was charged withethanol (130 mL) and pyridiniump-toluenesulfonate (1.14 g, 4.54 mmol),and the mixture was stirred at 50° C. for 4 days. The solvent wasconcentrated under reduced pressure, and thereafter the concentrate waspurified by silica gel column chromatography (hexane-ethyl acetate),thereby giving a product (S,S)-14 (13.3 g, 27.8 mmol) in the form of ayellowish oily product (yield: 85%).

¹H-NMR (270 MHz, CDCl₃, 30° C.) δ: 3.56 ppm (2H, dd, J=8.5, 9.5 Hz,—CH₂—), 3.69 (2H, dd, J=3.5, 9.5 Hz, —CH₂—), 3.73 (3H, s, OCH₃), 4.60(4H, s, benzyl), 4.94 (2H, dd, J=3.5, 8.5 Hz, methine), 7.28-7.40 (10H,m, Ph), 7.48 (2H, s, ArH)

EXAMPLE 5 Preparation of Crown Ether (S,S)-15

A 2-L three-neck flask was charged with 60% sodium hydride (3.57 g, 89.1mmol) under a nitrogen gas stream, and the paraffin was washed out withhexane. Anhydrous tetrahydrofuran (800 mL) was added thereto, and themixture was refluxed with heating. A mixed solution prepared bydissolving the compound 12 (6.52 g, 15.7 mmol) and the product (S,S)-14(7.38 g, 15.4 mmol) in anhydrous tetrahydrofuran (100 mL) was addeddropwise thereto over a period of 19 hours using a dropping funnelequipped with a needle. The mixture was heated at 65° C. for 22 hours,and thereafter water (50 mL) was added dropwise thereto in an ice bathto stop the reaction. The solution was concentrated under reducedpressure, and thereafter the residue was extracted with hexane-ethylacetate. The organic layer was washed with saturated brine, andthereafter the mixture obtained was dried over anhydrous magnesiumsulfate and concentrated, to give a reddish brown oily product (7.44 g).The product obtained was purified by silica gel column chromatography(hexane-ethyl acetate), thereby giving a product (S,S)-15 (2.21 g, 3.96mmol) in the form of a white bubbly solid (yield: 26%).

¹H-NMR (270 MHz, CDCl₃, 30° C.) δ: 3.42-3.68 ppm (12H, m, —OCH₂—), 4.26(3H, s, OCH₃), 4.52 (2H, d, J=8.6 Hz, methine), 4.44, 4.69 (4H, AB,J=10.0 Hz, benzyl), 7.28-7.37 (10H, m, Ph), 7.42 (2H, s, ArH)

EXAMPLE 6 Preparation of Crown Ether (S,S)-3

Inside a draft, a 300 mL three-neck flask was charged with anhydrousdimethylformamide (70 mL) under a nitrogen gas stream, and the contentwas cooled in an ice bath. Thereafter, 60% sodium hydride (1.79 g, 44.7mmol) was added thereto while stirring, and ethanethiol (7.0 mL, 92mmol) was added dropwise thereto from a syringe. Next, a solutionprepared by dissolving the product (S,S)-15 (1.90 g, 3.42 mmol) inanhydrous dimethylformamide (30 mL) was added dropwise to the mixtureover a period of 1 hour, and thereafter the mixture was stirred at 80°C. for 1 hour. Next, water (10 mL) was added thereto in the ice bath tostop the reaction, and 6 N hydrochloric acid was added to the mixtureobtained to neutralize the mixture. Thereafter, the mixture obtained wasextracted with chloroform. The organic layer was washed sequentiallywith an aqueous solution of Antiformin and with saturated brine. Themixture obtained was dried over anhydrous magnesium sulfate andconcentrated to give a brown oily product. The resulting product waspurified by silica gel column chromatography (hexane-ethyl acetate), andthen purified by recycling high-performance column chromatography,thereby giving a product (S,S)-3 (1.32 g, 2.43 mmol) (yield: 71%).

¹H-NMR (270 MHz, CDCl₃, 30° C.) δ: 3.55-3.80 ppm (12H, m, —OCH₂—), 4.65(2H, dd, J=3.1, 8.5 Hz, methine), 4.73 (4H, s, benzyl), 7.29-7.38 (12H,m, Ph, ArH)

EXAMPLE 7 Preparation of Crown Ether (S,S)-21

A 30 mL three-neck flask was equipped with septum and a ball condenser,and flame-dried under a nitrogen gas stream. The flask was equipped witha thermometer, and charged with copper (I) iodide (4.28 mg, 21.8 μmol)and dichlorobis(benzonitrile)palladium (II) (32.6 mg, 28.2 μmol), andthe atmosphere was replaced with argon. The product (S,S)-3 (505 mg, 929μmol), piperidine (5 mL) and tri-t-butylphosphine (20.0 μL, 73.8 μmol)were added thereto, and freeze-degassing was carried out. A solutionprepared by dissolving phenylacetylene (125 μL, 1.11 mmol) in piperidine(1 mL) was added dropwise thereto, and the mixture was stirred for 4hours at 40° C. Additional phenylacetylene (50 μL, 443 μmol) was added,and the mixture was stirred for additional 2 hours. Water (10 mL) wasadded in an ice bath to stop the reaction. The reaction solution wasextracted with ether. The organic layer was washed sequentially with 0.1N aqueous ammonium chloride solution, and with saturated brine. Themixture obtained was dried over anhydrous magnesium sulfate andconcentrated. Thereafter, the concentrate was purified sequentially bysilica gel column chromatography (hexane-chloroform), and recyclinghigh-performance liquid column chromatography, to give a product (S,S)-2(298 mg, 528 μmol) in the form of a beige color solid (yield: 57%).

¹H-NMR (270 MHz, CDCl₃, 30° C.) δ: 3.55-3.82 ppm (12H, m, —OCH₂—), 4.67(2H, dd, J=3.0, 8.6 Hz, methine), 4.76 (4H, s, benzyl), 7.25-7.39 (12H,m, ArH), 7.44-7.49 (2H, m, ArH), 8.40 (1H, s, OH)

¹³C-NMR (67.5 MHz, CDCl₃, 30° C.) δ: 156.0 ppm (4°), 138.5 (4°), 132.9(3°), 131.3 (3°), 128.4 (3°),128.2 (3°), 128.0 (3°), 127.7 (30), 126.8(3°), 124.8 (4°), 123.6 (4°), 114.0 (4°), 89.3 (4°), 87.8 (4°), 81.4(3°), 75.0 (2°), 70.6 (2°), 70.4 (2°), 69.0 (20)

IR (KBr cm⁻): 3334, 3059, 3029, 2901, 2864, 2208, 1594, 1493, 1477,1452, 1343, 1267, 1093, 755, 701

Specific rotation [α]²⁵ _(D)=+82.9 (c 1.02, CHCl₃)

Melting point: 52°-54° C.

MS (APCI) m/z 563 (M−H)⁻

From the above results, the optically active compound represented by theformula (II) was obtained from (S)-(+)-mandelic acid in an overall yieldof 8.5% through eight steps.

Next, complexation ability and enantiomer-recognizing ability of theoptically active compound represented by the formula (II) were evaluatedby using both enantiomers of 2-amino-1-propanol.

According to a titration experiment in CDCl₃ using the ¹H-NMR spectrum,the stability constant for complexation at 25° C. is 61 M⁻¹ with(R)-2-amino-1-propanol, and 14 M-1 with (S)-2-amino-1-propanol, andenantioselectivity as high as K_(R)/K_(S)=4.3 was observed. Whentitration was carried out in CHCl₃ using the UV-vis and fluorescenceemission spectra, there were confirmed that the resulting ammoniumphenolate salt-complex has absorption at about 330 nm, which is highlywell overlapped with the fluorescent spectrum of the compoundrepresented by the formula (II).

Therefore, it is anticipated that the stronger the complex formation,the larger the re-absorption, thereby amplifying selectivity. Therefore,the compound was excited at 312 nm, its isosbestic point, and itsfluorescence intensity was observed at 340 nm, its maximum fluorescencewavelength. From its Stern-Volmer plot, K_(SV) was obtained at 25° C. Asa result, K_(SV) is 6.6 M⁻¹ for (R)-2-amino-1-propanol, and 3.3 M⁻¹ for(S)-2-amino-1-propanol, the ratio being doubled. As described above,there was confirmed that the optically active compound represented bythe formula (II) itself is capable of amplifying enantiomer-recognizingability due to reabsorption of fluorescence emission by the complex.

As described above, there was confirmed that since the selectivity isamplified by synergistic functions of selectivity due to complexstability with both enantiomeric amines and selectivity as a quenchingagent of the complex formed by the enantiomeric amines, the opticallyactive compound of the present invention represented by the compoundrepresented by the formula (II) can serve as a chiral sensor having ahigh enantioselectivity.

INDUSTRIAL APPLICABILITY

Since the optically active compound of the present invention is capableof highly selectively recognizing a specified chiral compound in highsensitivity, the compound is very useful as a chiral sensor forpractical purposes.

1. An optically active compound having an unsaturated bond at anoptically active binding site, wherein the unsaturated bond and afluorescent substituent or a substituent capable of impartingfluorescence are united in a conjugated manner.
 2. The optically activecompound according to claim 1, wherein the compound is represented bythe formula (I):

wherein R¹ is an aromatic group or an aromatic ethynyl group; R² is ahydrogen atom or an alkyl group having 1 to 10 carbon atoms; each of R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ is independently a hydrogen atom, or analkyl group having 1 to 30 carbon atoms, a cyclic alkyl group having 3to 30 carbon atoms or an aryl group having 6 to 30 carbon atoms, each ofwhich may have a substituent, with proviso that each of R⁴ and R⁵, andR⁸ and R⁹ may be bonded to form an alkylene group having 2 to 60 carbonatoms; and each of R¹¹ and R¹² is independently a hydrogen atom or analkyl group having 1 to 15 carbon atoms which may have a hetero-atom,with proviso that R¹¹ and R¹² may be bonded to form an alkylene grouphaving 2 to 30 carbon atoms which may have a hetero-atom.
 3. A chiralsensor comprising the optically active compound as defined in claim 1 or2.